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The Journal of Neuroscience, February 23, 2005, 25(8):1943-1951; doi:10.1523/JNEUROSCI.4402-04.2005

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Neurobiology of Disease
Antiepileptic Effects of Botulinum Neurotoxin E

Laura Costantin,^1 * Yuri Bozzi,^2 * Cristina Richichi,³ Alessandro Viegi,¹ Flavia Antonucci,² Marcella Funicello,³ Marco Gobbi,³ Tiziana Mennini,³ Ornella Rossetto,⁴ Cesare Montecucco,⁴ Lamberto Maffei,^1,2 Annamaria Vezzani,³ and Matteo Caleo²

¹Scuola Normale Superiore and ²Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, 56100 Pisa, Italy, ³Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy, and ⁴Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, 35121 Padova, Italy

Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/E-injected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.

Key words: neurotransmitter release; kainic acid; seizures; Morris water maze; neuronal death; hippocampal kindling

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Received Aug 2, 2004; revised January 7, 2005; accepted January 7, 2005.

This article has been cited by other articles:

				P. P. Tripathi, L. G. Di Giovannantonio, A. Viegi, W. Wurst, A. Simeone, and Y. Bozzi Serotonin Hyperinnervation Abolishes Seizure Susceptibility in Otx2 Conditional Mutant Mice J. Neurosci., September 10, 2008; 28(37): 9271 - 9276. [Abstract] [Full Text] [PDF]

				F. Antonucci, C. Rossi, L. Gianfranceschi, O. Rossetto, and M. Caleo Long-Distance Retrograde Effects of Botulinum Neurotoxin A J. Neurosci., April 2, 2008; 28(14): 3689 - 3696. [Abstract] [Full Text] [PDF]

				M. Caleo, L. Restani, L. Gianfranceschi, L. Costantin, C. Rossi, O. Rossetto, C. Montecucco, and L. Maffei Transient Synaptic Silencing of Developing Striate Cortex Has Persistent Effects on Visual Function and Plasticity J. Neurosci., April 25, 2007; 27(17): 4530 - 4540. [Abstract] [Full Text] [PDF]

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